Skip to main content

Nonclinical AAV Biodistribution Study Consideration For Gene Therapy: ICH S12 Perspective

What is Biodistribution?

Biodistribution (BD) is the in vivo distribution, persistence, and clearance of a gene therapy (GT) product at the site of administration and in target and non-target tissues, including biofluids (e.g., blood, cerebrospinal fluid, vitreous fluid), in biologically relevant animal species. Nonclinical BD studies entail the use of analytical methods to detect the GT product and transferred genetic material in collected samples and can include methods to detect the expression product of the transferred genetic material.

Characterization of the BD profile following administration of a GT product in animals is a critical component of a nonclinical development program. BD characterization data are critical in:

  • overall interpretation of the study findings to enable a better understanding of the relationship of various findings (desired and undesired) to the administered GT product. 
  •  ascertaining a potential benefit: risk profile of the GT product before administration in humans. 
  • inform elements of a first-in-human trial and subsequent clinical trials, such as the dosing procedure (i.e., dosing intervals between subjects), the monitoring plan, and long-term follow-up assessment.

When BD studies should be conducted? 

BD studies should be conducted during the early stage of nonclinical development and prior to initiation of non-clinical studies. The BD data obtained may

  • aid in species selection for subsequent pharmacology and toxicology studies. 
  • help evaluating and interpreting the nonclinical pharmacology and toxicology findings. 
  • also inform design aspects of a first-in-human clinical trial
Is the GLP studies a requirement of BD studies?

In principle, nonclinical BD studies that are not conducted in compliance with Good Laboratory  Practice (GLP) are accepted; however, when BD evaluation is performed as part of a GLP compliant toxicology study, it is important that all in-life parameters and sample collection procedures remain in compliance with GLP

Does the Test Article needs to be the same used for clinical studies?
The test article administered in the nonclinical BD studies should be representative of the intended clinical GT product including:
  • manufacturing process, 
  • product characteristics (e.g., titre),
  • final clinical formulation. 
Nonclinical BD data generated with a GT product that consists of the clinical vector containing a different therapeutic transgene or an expression marker gene when 
  • e.g., adeno associated virus vector of the same serotype and
  • promoter with a fluorescent marker protein expression cassette 
What are the factors while selecting the animal model species? 
BD assessment should be conducted in a biologically relevant animal species or model that is permissive for transfer and expression of the genetic material. Selection factors may include 
  • species differences in tissue tropism.
  • gene transfer efficiency, and transgene expression in target.
  • and non-target tissues/cells. 
  • immunogenicity against the administered vector and/or expression product. 
How to determine the route of administration and dose? 
The ROA of the GT product can affect the BD profile, including the cell types that are transduced and the immune response. Therefore, the GT product should be administered using the intended clinical ROA, as feasible.
The selected dose levels of the administered GT product should provide adequate characterization of the BD profile to aid in interpretation of the pharmacology and toxicology assessments. The highest dose level administered should be the expected maximum dose level in the toxicology studies.

However, with appropriate justification, the anticipated maximum clinical dose level can also serve as the highest dose level for BD evaluation.

What sample specimen should be collected? 
The collected samples should include the following core panel of tissues/biofluids: blood, injection site(s), gonads, adrenal gland, brain, spinal cord (cervical, thoracic, and lumbar), liver, kidney, lung, heart, and spleen. 

Additional tissues (such as peripheral nerves, dorsal root ganglia, cerebrospinal fluid, vitreous fluid, draining lymph nodes, bone marrow, and/or eyes and optic nerve) may be collected depending on the following factors:
  • vector type/tropism 
  • expression product
  • route of administration, 
  • disease pathophysiology 
  • animal/sex and age

Reference 

https://www.fda.gov/media/151599/download

Labels:

Popular posts from this blog

Human Genome Editing: FDA Draft Guidance Summary

Consideration for Developing Gene Editing Product  1. Genome Editing Methods: Genome editing can be achieved through nuclease-dependent or nuclease-independent methods. Nuclease-dependent methods involve introducing site-specific breaks in DNA using technologies like zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), modified-homing endonucleases, and CRISPR-associated (Cas) nucleases. These breaks can lead to modification of the DNA sequence at the cleavage site. Nuclease-independent methods can change DNA sequences without cleaving the DNA and include techniques like base editing and synthetic triplex-forming peptide nucleic acids. The choice of GE technology should consider factors such as the mechanism of action, the ability to target specific DNA sequences, and the potential to optimize components for efficiency, specificity, or stability. 2. Type and Degree of Genomic Modification: Different GE approaches rely on DNA repair pathways such a...
Read more

Stem loop RT-PCR for Detection of siRNA in Animal Tissues

Step Loop RT-PCR for Detection of Small Interfering RNA (siRNA) The recent publications described a novel used the novel method for the detection of siRNAs using a TaqMan®-based approach. This approach utilizes similar strategy that has been used for microRNA detection. The approach is illustrated in below.  In brief, the RT step occurs in the presence of a stem-loop RT primer that is complementary to the last 6–10 bases of the 3′ end of the antisense strand of the target siRNA. The stem-loop primer contains an additional universal sequence at the 5′ end that facilitates a TaqMan-based detection strategy in the subsequent qPCR step. As in the case of microRNA, the forward primer for qPCR is sequence-specific for the target siRNA. For sequence compositions that yield a low predicted melting temperature (Tm), the forward primer is designed as a tailed primer to help increase Tm. Stem Loop PCR for SiRNA Detection Step 1: Preparation of liver and plasma samples for the quanti...
Read more

Human Gene Therapy for Neurodegenerative Diseases: FDA Guidance Summary

  Neurodegenerative diseases are a diverse group of disorders characterized by the progressive degeneration of the central or peripheral nervous system, and they can have various causes and clinical characteristics. This guidance document is a resource for sponsors on different aspects of product development, preclinical testing, and clinical trial design. It acknowledges the unique challenges and considerations associated with developing GT products for such complex and varied diseases. Below are the key summaries from the guidance. CONSIDERATIONS FOR CHEMISTRY, MANUFACTURING AND CONTROLS (CMC) The considerations for Chemistry, Manufacturing, and Controls (CMC) when developing gene therapy (GT) products for the treatment of neurodegenerative diseases are crucial for ensuring the safety and efficacy of these advanced therapies. Here, we will elaborate on the specific CMC considerations outlined in your text: Route of Administration and Product Volume: Neurodegenerative diseases oft...
Read more

FDA Guidance on Studying Multiple Versions of Cellular or Gene Therapy Products in Early-Phase Clinical Trials

 The purpose of this guidance is to offer advice to sponsors interested in conducting early-phase clinical trials for a single disease involving multiple variations of a cellular or gene therapy product. Sponsors aim to gather preliminary safety and efficacy data for these product variations within a single clinical trial. It's important to note that even though multiple product versions are studied together, each version is distinct and typically requires a separate investigational new drug application (IND) submission to the FDA. The primary goal of these early-phase clinical studies is to inform decisions about which product version(s) should be advanced for further development in later-phase trials. As such, these studies are not designed to provide the main evidence of effectiveness needed for a marketing application. They are generally not statistically powered to demonstrate a significant difference in efficacy between the different study arms. In this guidance, the FDA prov...
Read more

ICH Q8 (R2) Pharmaceutical development (CHMP/ICH/167068/04)

 ICH Q8 (R2) is a guideline titled "Pharmaceutical Development" (CHMP/ICH/167068/04). This guideline is part of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and provides recommendations for the pharmaceutical development of medicinal products. It offers a structured approach to the development of pharmaceutical products to ensure their quality, safety, and efficacy. Here's an elaboration of ICH Q8 (R2): 1. Purpose of ICH Q8 (R2): The primary purpose of ICH Q8 (R2) is to provide a systematic and science-based approach to pharmaceutical development. The guideline aims to facilitate the design and development of high-quality pharmaceutical products that meet the needs of patients and regulatory authorities. 2. Scope: ICH Q8 (R2) applies to the development of all types of pharmaceutical products, including small molecules, biotechnological products, and other complex medicinal products. 3. Pharmaceutical Develop...
Read more